Transdermal therapeutic system (tts) with fentanyl as a active ingredient

ABSTRACT

The invention relates to a transdermal therapeutic system (TTS), comprising a backing layer, which is permeable to the active ingredient, at least one matrix layer, comprising fentanyl or an active agent analogous to fentanyl, based on polyacrylate and a protective layer to be removed before usage, characterized in that the polyacrylate polyer is self-adhesive, free of carboxyl groups, has a saturation solubility for fentanyl of 3 to 20 wt. %, preferably of 4 to 12 and particularly of 5 to 10 wt. % and the layers contain at least 80% of the included active ingredient in a molecularly-dispersed, dissolved form.

[0001] The present invention relates to a transdermal therapeutic system(TTS) containing the active substance fentanyl.

[0002] Fentanyl and fentanyl analog derivatives such as sulfentanyl,carfentanyl, lofentanyl, and alfentanyl are extremely active analgesics.Their low dosage and their physicochemical properties such as, forexample, the n-octanol/water partition coefficient, the melting point,and the molecular weight make it possible to supply the substancestransdermally in an effective amount, and their pharmacokineticproperties such as the rapid metabolization and the relatively narrowtherapeutic index make their transdermal supply desirable.

[0003] Indeed, for a number of years a fentanyl TTS has been on themarket. This system is of the type known as a reservoir system. Areservoir system is a TTS which contains the active substance in aliquid or gel formulation in a pouch formed from an impermeable film anda membrane which is permeable for the active substance. The impermeablefilm acts as a backing layer, in order to prevent the liquid or gelformulation of the active substance emerging on the side of the pouchfacing away from the skin. The membrane serves to regulate the rate ofactive substance release from the skin-facing side of the pouch. On thisside, the membrane additionally possesses an adhesive layer forattaching the overall TTS to the skin.

[0004] In this specific case (Durogesic® TTS), fentanyl is in solutionin a mixture of ethanol and water. Further details of this system can befound in U.S. Pat. No. 4,588,580 or DE 35 26 339, both of which containa detailed description.

[0005] However, reservoir systems have a major disadvantage, namely thatin the event of a leak (e.g., a simple mechanically induced damage, acut or tear, splitting of the weld seam, etc.) in the pouch containingthe active substance formulation, the active substance may come intocontact with the skin over a large area and, as a consequence of thiscontact, may be absorbed in, excessive doses. Especially in the case offentanyl and the fentanyl analog derivatives, this is potentially fatal,since overdose leads very rapidly to respiratory depression and hencefatal incidents. A number of such fatal or near-fatal incidents havebeen described in Clinical Pharmnacokine. 2000, 38 (1), 59-89.

[0006] It is an object of the present invention to provide a transdermaltherapeutic system comprising the active substance fentanyl and/orfentanyl analog derivatives which offers the user increased securityagainst inadvertent overdose.

[0007] This object is achieved by means of a transdermal therapeuticsystem which comprises a backing layer, an active substance layer, and aprotective layer, to be removed before use. The active substance layeris composed of a polymer into which a multiplicity of liquidmicroreservoirs have been incorporated. These microreservoirs containthe active substance.

[0008] As has been found, despite the fact that the active substance iscontained in a liquid formulation within the active substance layer,said layer is absolutely leakproof even when damaged mechanically (cuts,tears, abrasion, etc.). The user is therefore at no risk in respect ofuncontrolled release or inadvertent overdose as a consequence ofunintended or deliberate damage to the active substance layer.

[0009] From a purely external standpoint, there is no difference betweenthis kind of transdermnal therapeutic system and the second major TTStype, a matrix system. With the TTS of the invention, the internalstructure of the active substance layer can be perceived only under themicroscope. The liquid microreservoirs are embedded in the form of smalldroplets in the (preferably self-adhesive) active substance layer.(These droplets adopt an approximately spherical form.) A transdermaltherapeutic system with an active substance layer constructed in thisway will be referred to hereinbelow as a “microreservoir system”.

[0010] These liquid microreservoirs have an average diameter of about5-50 μm. In any case, however, they must be smaller than the thicknessof the active substance layer, since otherwise the active substanceliquid could escape. The size of the microreservoirs can be influencedby the choice of suitable liquids and by regulating certain parametersduring the preparation process.

[0011] Like a matrix system, the microreservoir system of the inventionis thus composed at its most simple of three layers: a backing layer,impermeable to the active substance; the self-adhesive active substancelayer, with the microreservoirs; and a protective layer, to be removedbefore use. A system of this kind is illustrated in FIG. 1.

[0012] Even in the case of a microreservoir system, however, it may benecessary in certain circumstances to limit the amount of activesubstance to be delivered by the transdermal therapeutic system over acertain period of time. This can be achieved by means of a membranewhich adjoins the active substance layer on the skin side, and which forattachment to the skin may additionally be provided with an adhesivelayer. During the preparation process, this skin-side adhesive layer maybe provided with a limited amount of active substance which, followingapplication of such a microreservoir system, is delivered to the skinand hence into the organism in a way which cannot be controlled by themembrane. The purpose of this measure is to shorten the time until atherapeutic plasma level is reached (known as the “lag time”). Amicroreservoir system with membrane is depicted in FIG. 2.

[0013] Suitable active substances include fentanyl and/or fentanylanalog derivatives, preferably sulfentanyl, carfentanyl, lofentanyl, andalfentanyl. The active substance is preferably in the form of the freebase; altematively, it may be used in the form of a pharmaceuticallyacceptable salt or as a mixture of the free base with a pharmaceuticallyacceptable salt of said base. Examples of suitable salts include thehydrochlorides, hydrobromides, sulfates, hydrogen sulfates, citrates,and tartrates.

[0014] As already mentioned, fentanyl and the fentanyl analogderivatives possess a narrow therapeutic index. This means that theactive substance release rate of a transdermal therapeutic systemcontaining fentanyl or a fentanyl analog must be controlled with verygreat precision.

[0015] It has been found that the polymer or polymer blend whichprovides the active substance layer with its internal cohesion, and inwhich the microreservoirs are embedded, must meet certain requirementsregarding dissolution capacity for the active substance and miscibilitywith the liquids which form the microreservoirs. Accordingly, thedissolution capacity for the active substance should be low, so is thatthe majority of the active substance is located within themicroreservoirs and not in the polymer itself. Further, the polymershould be substantially immiscible with the liquids which form themicroreservoirs. These measures ensure that, first, the formation ofmicroreservoirs is actually possible and that, secondly, the dissolutioncapacity of the polymer phase for the active substance is not too high.

[0016] Polymers which have been found to be suitable include hydrophobicpolymers, which preferably possess pressure sensitive adhesion. Theseinclude polyisobutylenes and silicones (polysiloxanes). Amine-resistantpolysiloxanes have proven particularly suitable. In solubility studiesit has been found that the solubility of the active substance in suchpolymers is low. For example, fentanyl in base form has a solubility insuch polymers of less than 0.5% by weight.

[0017] Amine-resistant polymers of this kind are produced, for example,by Dow Corning and are sold under the trade name BIO-PSA. The tackinessof these polymers ranges from nontacky via moderately strongly tostrongly tacky, the appropriate tack also being adjustable by blendingof the individual types and/or by adding low molecular mass substancessuch as silicone oil, for example.

[0018] The advantage of the amine-resistant polysiloxanes is that theypossess no free siloxanol groups and therefore do not tend to undergocondensation reactions in the presence of basic active substances orsalts of basic active substances, with adverse consequences for the bondstrength. Moreover, the interaction with the polar groups of the activesubstance molecules is lessened.

[0019] Solvents which can be used for the polymer include low-polarityand/or hydrophobic solvents. Amine-resistant polysiloxanes are offeredin a variety of solvent systems. The most suitable solvents for theproduction of transdermal therapeutic systems in the context of thisinvention are n-heptane and comparable hydrocarbons, since the liquidsenvisaged for the microreservoirs are of only poor miscibility with thissolvent.

[0020] As a result, during preparation, the solution of the activesubstance in the micro-reservoir liquid can be dispersed in the solutionof the polysiloxane and thus the size of the microreservoirs in thecomposition to be coated can be set at this stage by virtue of thestirring conditions. For the purposes of the present description, adispersion is a system which is composed of a continuous phase (which ismade of polymer) and of the microreservoirs, which are not mutuallycontiguous (and which are made up of the liquid droplets).

[0021] The liquid, which constitutes an important ingredient of themicroreservoirs, should be at least partly miscible both with water andwith organic solvents. It may therefore also be referred to asambiphilic.

[0022] Moreover, the liquid should possess a good solvency for theactive substance, in order to accommodate the required amount of activesubstance in customary TTS active substance layer thicknesses of about30 to 300 μm, correspond to a coating weight of 30-300 g/m².

[0023] Dipropylene glycol, diethylene glycol monoethyl ether, diethyleneglycol diethyl ether, diethylene glycol monomethyl ether, diethyleneglycol dimethyl ether, 1,3-butanediol,2,2-dimethyl4-hydroxymethyl-1,3-dioxolane, 2-pyrrolidone, andN-methylpyrrolidone have proven particularly suitable. Instead of thesubstances alone it is of course also possible to take blends thereof.

[0024] The saturation solubilities of fentanyl, measured in differentliquids suitable for use as the microreservoirs, are shown in table 1.TABLE 1 Saturation solubility of fentanyl in different liquidsMicroreservoir liquid Solubility [% w/w] 1,3-Butanediol 10 Dipropyleneglycol 18 Transcutol* 25 Diethylene glycol diethyl ether 26N-Methylpyrrolidone 26

[0025] Accordingly, the solubility of fentanyl in base form is higher bya factor of about is 20-50 in the liquids envisaged for themicroreservoirs than in the polysiloxane polymer. This is more thansufficient to accommodate the required amount of active substance withina microreservoir matrix not exceeding 200 μm in thickness, in a systemwith an acceptable areal size.

[0026] The high solubility of fentanyl in the liquids envisaged for themicroreservoirs coupled with its low solubility in the silicone polymerhas the effect, moreover, that by far the predominant portion of thefentanyl is actually located within the microreservoirs and not insolution in the polymer phase.

[0027] Prior to application of a TTS of the invention, preferably morethan 50% of the total active substance present in the TTS is situatedwithin the microreservoirs, since otherwise, because of the poorsolubility in the polymer, the active substance layers are too thick andthe service properties poor for the finished system.

[0028] The total concentration of the active substance in the activesubstance layer is only between 2 and 5% by weight, which then alsocorresponds approximately to the saturation concentration of the activesubstance in the polymer. This means that, despite the lowconcentration, the thermodynamic activity of the active substance is ata maximum, i.e., at or just below 1.

[0029] The fraction of the microreservoirs in the active substance layermay amount to up to 40% by weight, although it is advantageous not toexceed 30% by weight.

[0030] It has proven advantageous to add to these liquids a substancewhich raises their viscosity. Such substances may comprise polymerswhich are capable of forming a gel with the liquid. Mention may be madeby way of example of ethylcellulose and hydroxypropylcellulose, whichare also used in the examples. This measure facilitates thedispersibility of the liquid in the solution of the polymer and may alsoresult in smaller microreservoir diameters.

[0031] For microreservoir systems of the invention which are providedwith a membrane, either microporous membranes or what are known asdistribution membranes may be used. Microporous membranes are filmsprovided with microscopic pores or channels. Here, the transport ofactive substance is substantially through these pores or channels, whichmust therefore be filled with a medium which is diffusible for theactive substance (e.g., a liquid, gas, gel or other material). Thenumber, the internal surface area, and the size of the pores, and thephysicochemical properties of the pore or channel filling substantiallydetermine the release of active substance (permeation rate).

[0032] Distribution membranes do not possess any pores; in other words,the active substance must diffuse through the membrane material itself.When membranes of this kind are used, it is the thickness of themembrane, and the solubility and diffusion coefficient of the activesubstance in the membrane material, which determine the release ofactive substance. Distribution membranes which have proven particularlyhighly suitable are those based on copolymers of ethylene and vinylacetate (EVA). Membranes of this kind are available in a variety ofthicknesses and with different compositions. Customary thicknesses rangebetween 20 and 150 μm, and the vinyl acetate (VA) content between 2 and25% by weight.

[0033] Since the VA content has an effect on the solubility and thediffusion coefficient of the active substances in the EVA polymers, itis a further important membrane characterization parameter wheremembranes made of this material are being used. In the examples, amembrane 50 μm thick with a VA content of 9% by weight has been used.The permeation rates achieved using this membrane can be raised throughthe use of thinner membranes or membranes having a higher VA content.Naturally, the use of thicker membranes and the reduction of the VAcontent has the opposite effect.

[0034] Especially when systems without membrane control are used, theactive substance intake, i.e., the amount of active substance deliveredby the TTS that is actually absorbed via the skin into the bloodcirculation is also dependent on the permeability of the skin. The outerskin layer in particular, the stratum corneum, forms the principalbarrier against penetrative active substances. This barrier function canbe lowered through the use of what are called enhancers, therebyincreasing the active substance intake. Enhancers are known to theskilled worker, for example, from the publication “Skin penetrationenhancers cited in the technical literature” by David W. Osborne andJill J. Henke, ViroTex Corporation, which can be called up on theInternet at http://www.pharmtech.com/technical/osborne/osborne.htm andwhich in order to avoid repetition is intended in its entirety to formpart of the disclosure content of this specification.

[0035] For the transdermal therapeutic systems of the present inventionit is possible with particular advantage to use fatty acid, fatty acidester, fatty alcohol or glycerol ester enhancers, especially whenfentanyl is the active substance being used.

[0036] For the preparation of the active substance layer, the activesubstance is dissolved in the liquid which forms the microreservoirs,and this solution is dispersed in the solution of the polymer. Theresulting dispersion is then used to coat an appropriatesubstrate—normally a polyester film with an abhesive coating—and thesolvent of the polymer is removed by drying. The drying conditionsshould be chosen such that only a small proportion if any of themicroreservoir solvent is removed. It has been found that the liquid andthe solvent are preferably selected such that the solvent possesses aboiling temperature which is at least about 30°, with particularpreference at least 50°, below the boiling temperature of the liquid.

[0037] The dry matrix film is then laminated to the backing layer of thesystem—usually an active substance impermeable film with a thickness ofabout 15 -30 μm—and the individual transdermal therapeutic systems arethen punched from the overall laminate obtained.

[0038] The production of corresponding microreservoir systems comprisingmembranes is somewhat more complicated, but in terms of the coating andlaminating process is no different from the production of known systemswith the same layer sequence. In the examples, the production ofmicroreservoir systems with and without membranes is described indetail.

[0039] Using three transdermal therapeutic systems provided by thisinvention, i.e. microreservoir systems with and without membranes,permeation studies were conducted using human epidermis and Franzdiffusion cells, which are known to the skilled worker. The compositionand the results are summarized in tables 2 to 5, with the preparationprocess described in detail in the examples. TABLE 2 Composition of themicroreservoir systems without membranes Composition [% w/w] FormulationA B C Ingredients Fentanyl base 2.0 3.6 5.0 BIO-PSA 4301* 80.0 80.0 801,3-Butanediol 17.46 Dipropylene glycol 16.07 Transcutol** 14.4Hydroxypropyl-cellulose 0.54 0.33 Ethylcellulose 100NF 0.6 Coatingweight [g/m²] 130 85 65 Matrix thickness, 140 95 75 approx. [μm]

[0040] TABLE 3 Results of the permeation study with formulations A, Band C Average Cumulative permeated release fentanyl base [μg/cm²]* rateFormulation 4 h 8 h 24 h 48 h 72 h [μg/cm² * h] D [sic] 1.2 9.5 84.4194.0 275.0 3.82 E [sic] 1.12 8.87 75.80 191.00 283.00 3.93 F [sic]16.20 45.20 131.00 212.00 262.00 3.64

[0041] TABLE 4 Composition of the systems with control membraneComposition [% w/w] Formulation D E F Ingredients Reservoir layerFentanyl base 2.0 3.6 5.0 BIO-PSA 4301* 80.0 80.0 80 1,3-Butanediol17.46 Dipropylene glycol 16.07 Transcutol** 14.4 Hydroxypropyl-cellulose0.54 0.33 Ethylcellulose 100NF 0.6 Coating weight [g/m²] 130 85 65Control membrane EVA membrane 50 μm, 9% VA Skin contact layer BIO-PSA4301* 100 100 100 Coating weight [g/m²] 35 35 35

[0042] TABLE 5 Results of the permeation study with formulations D, Eand F Average Cumulative permeated release fentanyl base [μg/cm²]* rateFormulation 4 h 8 h 24 h 48 h 72 h [μg/cm² * h] D 1.4 4.9 26.2 64.0 99.81.39 E 2.7 8.1 37.0 85.0 129.0 1.79 F 0.8 4.7 45.3 114.0 166.0 2.31

[0043] Comparing the permeation results of the microreservoir systemswith and without a membrane it can be seen that the amount of activesubstance permeated after 72 hours is much lower in the case of themembrane systems, despite the active substance layers having the samecomposition. This can be attributed to the controlling effect of themembrane, which limits the delivery of active substance to a maximumirrespective of the particular nature of the skin.

[0044] The graphs (FIGS. 3 and 4) also reveal that, as the result of theuse of a membrane, the permeation profile is more linear and hence alsothe active substance intake in vivo is more uniform over the period ofuse. It is particularly evident in the case of formulation C, whichshows the highest permeation rate.

[0045] The TTS present on the market (Durogesic®) is available in 4strengths with average delivery rates of 25, 50, 75, and 100 μm/hour.With these figures and the results of the permeation studies, it ispossible to calculate the surface areas of the systems with ease. Theresults are summarized in table 6. TABLE 6 Calculated system surfaceareas of formulations A-F Delivery Calculated areal sizes [cm²] rate A BC D E F 25 μm/h 6.5 6.4 6.9 18.0 14.0 11.8 50 μm/h 13.0 12.8 13.8 36.028.0 23.6 75 μm/h 19.5 19.2 20.7 54.0 42.0 35.4 100 μm/h  26.0 25.6 27.672.0 56.0 47.2

[0046] The calculated surface areas all lie within an acceptable range.The size of the microreservoir systems with membrane can be made smallerstill through the use of thinner membranes or membranes with a higher VAcontent, although in that case the control of the delivery of activesubstance by the membrane will be less effective.

[0047] Microreservoir systems as provided by this invention thereforeshow very good permeation rates, which without a control membrane leadto TTS which are small in terms of area and are pleasant to wear. At thesame time, there is absolutely no possibility of any risk to the patientfrom excessive active substance intake due to leakage.

[0048] In the case of microreservoir systems with membranes, themembrane control which limits the delivery of active substance resultsin patch sizes which are larger but still acceptable.

[0049] All in all, therefore, microreservoir systems for fentanyl andthe fentanyl analog derivatives constitute a decisive step forward interms of wear comfort and patient safety from the known prior art.

[0050] The preparation examples which follow describe the preparation ofmicroreservoir systems with and without membranes.

EXAMPLE 1 Microreservoir System with 1,3-butanediol as Liquid,Formulation A

[0051] 1 g of fentanyl base is dissolved in 9 g of 1,3-butanediol,thickened with 3% hydroxypropylcellulose. To this solution there areadded 54.8 g of a 73% strength solution of an amine-resistant siliconeadhesive in n-heptane (BIO-PSA 4301, Dow Corning) and the activesubstance solution is dispersed in the solution of the silicone adhesiveby rapid stirring. The dispersion is then knife-coated onto anabhesively coated film, the protective layer to be removed later priorto use (Scotchpak 1022, 3M), in a thickness which following removal ofthe n-heptane by drying at 30° C. for 15 minutes results in a coatingweight of 135 g/m². The dry film is then laminated with the activesubstance impermeable backing layer (Scotchpak 1220, 3M) and thefinished transdermal therapeutic system is punched from the overalllaminate which results.

EXAMPLE 2 Microreservoir System with dipropylene glycol as Liquid,Formulation B

[0052] 1 g of fentanyl base is dissolved in 4.6 g of dipropylene glycol,thickened with 2% hydroxypropylcellulose. To this solution there areadded 30.5 g of a 73% strength solution of an amine-resistant siliconeadhesive in n-heptane (BIO-PSA 4301, Dow Corning) and the activesubstance solution is dispersed in the solution of the silicone adhesiveby rapid stirring. The dispersion is then knife-coated onto anabhisively coated film, the protective layer to be removed later priorto use (Scotchpak 1022, 3M), in a thickness which following removal ofthe n-heptane by drying at 30° C. for 15 minutes results in a coatingweight of 85 g/m². The dry film is then laminated with the activesubstance impermeable backing layer (Scotchpak 1220, 3M) and thefinished transdermal therapeutic system is punched from the overalllaminate which results.

EXAMPLE 3 Microreservoir System with Transcutol as Liquid, Formulation C

[0053] 1 g of fentanyl base is dissolved in 3 g of Transcutol, thickenedwith 4% ethylcellulose. To this solution there are added 22 g of a 73%strength solution of an amine-resistant silicone adhesive in n-heptane(BIO-PSA 4301, Dow Corning), and the active substance solution isdispersed in the solution of the silicone adhesive by rapid stirring.The dispersion is then knife-coated onto an abhesively coated film, theprotective layer to be removed later prior to use (Scotchpak 1022, 3M),in a thickness which following removal of the n-heptane by drying at 30°C. for 15 minutes results in a coating weight of 65 g/m². The dry filmis then laminated with the active substance impermeable backing layer(Scotchpak 1220, 3M) and the finished transdermal therapeutic system ispunched from the overall laminate which results.

EXAMPLES 4-6 Microreservoir Systems with Membranes, Formulations D, E,and F

[0054] The solution of an amine-resistant silicone adhesive (BIO-PSA4301, Dow Corning) is knife-coated to an abhesively coated film(Scotchpak 1022, 3M) in a thickness such that removal of the n-heptaneby drying at 30° C. for 15 minutes gives a coating weight of 20 g/m².The dried film is laminated with a membrane (EVA, 50 μm, 9% VA, 3M).

[0055] The protective layer is removed from the laminates from examples1-3 and the laminate consisting of active substance layer and backinglayer is laminated onto this membrane. The resulting overall laminate(formulations D, E and F) are then punched to give the finishedtransdermal therapeutic systems.

[0056] In the figures, the elements shown are as follows:

[0057]1=backing layer

[0058]2=active substance layer with microreservoirs

[0059]3=microreservoir

[0060]4=control membrane

[0061]5=skin contact layer

[0062]6=removable protective layer

1. A transdermal therapeutic system (TTS) comprising an active substance impermeable backing layer, an active substance layer, the active substance being fentanyl and/or a fentanyl analog derivative and/or a salt of fentanyl and/or a salt of a fentanyl analog derivative, and a protective layer, which needs to be removed before use, characterized in that said active substance layer comprises a polymer with microreservoirs dispersed therein.
 2. The TTS of claim 1, characterized in that the polymer is a pressure sensitive adhesive polymer.
 3. The TTS of claim 1 or 2, characterized in that the polymer is an amine-resistamt polysiloxane.
 4. The TTS of one or more of the preceding claims, characterized in that the microreservoirs contain a liquid.
 5. The TTS of any of the preceding claims, characterized in that the active substance is present completely dissolved in the microreservoirs.
 6. The TTS of one or more of the preceding claims, characterized in that at least 50% of the active substance in the TTS is contained within the microreservoirs.
 7. The TTS of one or more of the preceding claims, characterized in that the liquid comprises dipropylene glycol, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, 1,3-butanediol, 2,2-dimethyl4-hydroxymethyl-1,3-dioxolane, 2-pyrrolidone or N-methylpyrrolidone or a combination thereof.
 8. The TTS of one or more the preceding claims, characterized in that the liquid comprises an additive which increases the viscosity, preferably ethylcellulose or hydroxypropylcellulose.
 9. The TTS of one or more of the preceding claims, characterized in that the concentration of the active substance in the active substance layer is below 5% by weight, preferably below 4% by weight.
 10. The TTS of one or more of the preceding claims, characterized in that the weight of the active substance layer per unit area is between 30 and 300 g/m².
 11. The TTS of one or more of the preceding claims, characterized in that it comprises a membrane and, where appropriate, an adhesive layer.
 12. The TTS of claim 11, characterized in that the membrane is composed of an ethylene-vinyl acetate copolymer or of a microporous film based on polyethylene or polypropylene.
 13. The TTS of claim 12, characterized in that the ethylene-vinyl acetate copolymer has a vinyl acetate content of 2-25% and a thickness of between 20 and 150 μm.
 14. The TTS of one or more of the preceding claims, characterized in that the active substance layer further comprises a substance which enhances the rate of permeation through human skin.
 15. The TTS of claim 14, characterized in that the substance belongs to the group consisting of fatty acids, fatty acid esters, fatty alcohols, and glycerol esters. 